Advances in cystic fibrosis (CF) treatment have been realized largely through additional treatments and medications. Chronic oral azithromycin and inhaled tobramycin are two important medications strongly supported in consensus treatment guidelines for CF patients with P. aeruginosa (P.a.) airway infection. The large majority of people with CF eventually develop chronic airway infection with P.a.; therefore, over half of all patients with CF will likely be prescribed concomitant azithromycin and inhaled tobramycin, chronically. The beneficial effects of inhaled tobramycin have significantly decreased in clinical trials over the last 15 years without clear explanation. This parallels the introduction and rapid incorporation of oral azithromycin into treatment regimens. Our recent preclinical and clinical research strongly suggests that azithromycin can inhibit the anti-pseudomonal effects of tobramycin, associating with poor clinical response to inhaled therapy. Through registry query, we find that 75% of CF patients in the US who are prescribed inhaled tobramycin are also now prescribed azithromycin. It is therefore critically important to the CF research and clinical care community to definitively determine if azithromycin inhibits the previously observed health benefits of inhaled tobramycin in patients with P.a. airway infection. Through a double-blinded, randomized, placebo-controlled, crossover withdrawal study of azithromycin in CF subjects who continue cycled, inhaled tobramycin, we will test the impact of combining azithromycin with inhaled tobramycin therapy. Our primary outcome will be the change in FEV1 in response to 4 weeks of inhaled tobramycin, comparing a period of combination of inhaled tobramycin with azithromycin vs. placebo. Secondary outcome measures compared during the same two periods will include: change in patient reported quality of life and sputum P.a. bacterial density. Exploratory outcomes will include time to need antibiotics outside of study protocol and safety. This multi-center study, developed by an experienced team of investigators and the CF national data coordinating center, will generate necessary data to either support the ongoing widespread practice of combined azithromycin and inhaled tobramycin, or definitive reason to consider changing care recommendations for over half of all CF patients. It will also inform future clinical trials with combination antibiotic therapy and critically support ongoing and future mechanistic research.